@article {Jiang2547,
author = {Jiang, Jing and Goel, Raghav and Iftekhar, M. Arif and Visaria, Rachana and Belcher, John D. and Vercellotti, Gregory M. and Bischof, John C.},
title = {Tumor necrosis factor-α{\textendash}induced accentuation in cryoinjury: mechanisms in vitro and in vivo},
volume = {7},
number = {8},
pages = {2547--2555},
year = {2008},
doi = {10.1158/1535-7163.MCT-07-2421},
publisher = {American Association for Cancer Research},
abstract = {Cryosurgical treatment of solid cancer can be greatly assisted by further translation of our finding that a cytokine adjuvant tumor necrosis factor-α (TNF-α) can achieve complete cancer destruction out to the intraoperatively imaged iceball edge (-0.5{\textdegree}C) over the current clinical recommendation of reaching temperatures lower than -40{\textdegree}C. The present study investigates the cellular and tissue level dose dependency and molecular mechanisms of TNF-α-induced enhancement in cryosurgical cancer destruction. Microvascular endothelial MVEC and human prostate cancer LNCaP Pro 5 (LNCaP) cells were frozen as monolayers in the presence of TNF-α. Normal skin and LNCaP tumor grown in a nude mouse model were also frozen at different TNF-α doses. Molecular mechanisms were investigated by using specific inhibitors to block nuclear factor-κB{\textendash}mediated inflammatory or caspase-mediated apoptosis pathways. The amount of cryoinjury increased in a dose-dependent manner with TNF-α both in vitro and in vivo. MVEC were found to be more cryosensitive than LNCaP cells in both the presence and the absence of TNF-α. The augmentation in vivo was significantly greater than that in vitro, with complete cell death up to the iceball edge in tumor tissue at local TNF-α doses greater than 200 ng. The inhibition assays showed contrasting results with caspase-mediated apoptosis as the dominant mechanism in MVEC in vitro and nuclear factor-κB{\textendash}mediated inflammatory mechanisms within the microvasculatures the dominant mechanism in vivo. These results suggest the involvement of endothelial-mediated injury and inflammation as the critical mechanisms in cryoinjury and the use of vascular-targeting molecules such as TNF-α to enhance tumor killing and achieve the clinical goal of complete cell death within an iceball. [Mol Cancer Ther 2008;7(7):2547{\textendash}55]},
issn = {1535-7163},
URL = {https://mct.aacrjournals.org/content/7/8/2547},
eprint = {https://mct.aacrjournals.org/content/7/8/2547.full.pdf},
journal = {Molecular Cancer Therapeutics}
}